Tumor Targeting Synergistic Drug Delivery by Self-Assembled Hybrid Nanovesicles to Overcome Drug Resistance.

PURPOSE: To overcome multi-drug resistance (MDR) in tumor chemotherapy, a polymer/inorganic hybrid drug delivery platform with tumor targeting property and enhanced cell uptake efficiency was developed. METHOD: To evaluate the applicability of our delivery platform for the delivery of different drug resistance inhibitors, two kinds of dual-drug pairs (doxorubicin/buthionine sulfoximine and doxorubicin/tariquidar, respectively) were loaded in heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles to realize simultaneous delivery of an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells. RESULTS: Prepared by self-assembly, the drug loaded hybrid nanovesicles with a mean size less than 210 nm and a negative zeta potential exhibit good stability in serum contained aqueous media. The in vitro cytotoxicity evaluation indicates that hybrid nanovesicles with tumor targeting biotin moieties have an enhanced tumor cell inhibitory effect. In addition, dual-drug loaded hybrid nanovesicles exhibit significantly stronger cell growth inhibition as compared with doxorubicin (DOX) mono-drug loaded nanovesicles due to the reduced intracellular glutathione (GSH) content by buthionine sulfoximine (BSO) or the P-glycoprotein (P-gp) inhibition by tariquidar (TQR). CONCLUSIONS: The tumor targeting nanovesicles prepared in this study, which can simultaneously deliver multiple drugs and effectively reverse drug resistance, have promising applications in drug delivery for tumor treatments. The polymer/inorganic hybrid drug delivery platform developed in this study has good applicability for the co-delivery of different anti-tumor drug/drug resistance inhibitor pairs to overcome MDR. Graphical Abstract A polymer/inorganic hybrid drug delivery platform with enhanced cell uptake was developed for tumor targeting synergistic drug delivery. The heparin-biotin/heparin/protamine sulfate/calcium carbonate nanovesicles prepared in this study can deliver an anticancer drug and a drug resistance inhibitor into drug-resistant tumor cells simultaneously to overcome drug resistance efficiently.

Doxorubicin loaded tumor-triggered targeting ammonium bicarbonate liposomes for tumor-specific drug delivery.

Ammonium bicarbonate (ABC) liposomes can only release drugs extracellularly while intracellular drug delivery could be more promising than extracellular release in chemotherapy. The purpose of this work was to endow the ABC liposomes with tumor-triggered targeting effect, to realize the intracellular drug release and retain the long circulation characteristics of the liposomes. The tumor-triggered targeting ABC (TT-ABC) liposomes were proposed to improve uptake of tumor cells owing to folate (FA) - specific binding. To retain the long circulation characteristics of the TT-ABC liposomes, we synthesized PEGylated phospholipid with a pH-sensitive imine bond (DSPE-PEG5000) and added it to the liposomes. After endocytosis by tumor cells via active targeting, the TT-ABC liposomes produced carbon dioxide (CO2) bubbles at elevated temperature or in the acidic endo/lysosome. The permeable defects could be created in the phospholipid bilayer by the generating CO2 bubbles, so the liposomes could quickly release the drugs intracellularly. Doxorubicin (DOX) loaded TT-ABC (DOX@TT-ABC) liposomes exhibited good stability at physiological pH (7.4) and released DOX quickly at reduced pH (6.4) and hyperthermia (42 °C). DOX@TT-ABC liposomes showed significantly enhanced cellular uptake, intracellular accumulation of DOX, and cytotoxicity at pH 6.4 and 42 °C.

Let-7b regulates alpaca hair growth by downregulating ectodysplasin A.

Hypohidrotic ectodermal dysplasia (HED), also known as anhidrotic ectodermal dysplasia, is characterized by the clinical manifestations of less sweat or no sweat, sparse or no hair, tooth agenesis and/or abnormal tooth morphology. The characteristics of alpaca ear hair differ from the back hair. The ectodysplasin A (EDA) signaling pathway has a regulatory effect on skin development and hair growth. The aim of the present study was to study the effects of EDA on alpaca hair growth by examining the mRNA and protein expression levels of EDA in alpaca ear and back skin by reverse transcription­quantitative polymerase chain reaction and western blot analysis, respectively. Results indicated that EDA expression was higher in the ear skin compared with the back skin. The expression levels of let­7b in the skin of healthy alpacas varies; the difference between let­7b expression levels of the ear and back have been reported to be >2­fold, suggesting a role for let­7b in the development of adult alpaca skin and hair follicles. A dual­luciferase reporter vector was constructed to verify the targeting relationship between microRNA let­7b and EDA, and the results revealed that EDA was a target gene of let­7b. Alpaca skin fibroblasts were transfected with a let­7b eukaryotic expression vector to investigate the regulatory relationship between let­7b and EDA. The expression of EDA was decreased in the transfected group; immunocytochemical results demonstrated that the EDA protein was abundantly expressed in the fibroblast cytoplasm. EDA protein expression was weaker in the transfected cells than in the untransfected cells. These results suggested that EDA may serve a role in alpaca hair growth and is probably a target gene of let­7b; let­7b downregulated EDA mRNA and protein expressions, which suggested that let­7b may regulate alpaca hair growth. These conclusions suggested that let­7b may be associated with HED.

Epidemiology of 45,616 suspect cases of Hand, Foot and Mouth Disease in Chongqing, China, 2011-2015.

Epidemiology and etiology of hand, foot, and mouth disease (HFMD) based on large sample size or evaluation of detection for more enterovirus serotypes are not well investigated in Chongqing of China. 45,616 suspect HFMD patients were prospectively enrolled among whom 21,615 were laboratory confirmed HFMD cases over a 5-year period (January 2011 to December 2015). Their epidemiological, clinical, and laboratory data were extracted and stratified by month, age, sex, disease severity, and enterovirus serotype. Subsequently 292 non-EV-A71/CV-A16 HFMD confirmed cases were randomly selected in three consecutive outbreaks to detect CV-A6 and CV-A10, using RT-PCR. Results showed that the HFMD epidemic peaked in early summer and autumn. The median age of onset was 2.45 years with a male-to-female ratio of 1.54:1, and with children under 5 years of age accounting for 92.54% of all confirmed cases. EV-A71 and CV-A16 infection accounted for only 36.05% (7793/21615) of total confirmed cases while EV-A71 accounted for 59.64% (232/389) of severe cases. Importantly, the proportion of EV-A71 infection generally increased with age which showed rapid growth in severe cases. CV-A6 and CV-A10 were tested positive in Chongqing, but CV-A6 had greater positive rates of 62.33% while CV-A10 had 4.79% in non-EV-A71/CV-A16 HFMD confirmed cases.

[Onyx embolization for treatment of dural arteriovenous fistula: comparison of long- distance versus routine injection method].

OBJECTIVE: To compare the efficacy, clinical characteristics, safety, injection time and radiation exposure of Onyx embolization using a long-distance injection method and routine injection method for management of dural arteriovenous fistula (DAVF). METHODS: The clinical data were retrospectively analyzed in 59 patients with DAVF treated with Onyx embolization using long-distance injection method (28 patients) and routine injection method (31 patients). The efficacy, safety, injection time and radiation exposure during Onyx embolization were compared between the two injections methods. RESULTS: The average radiation dose exposure to the surgeon per procedure was significantly lower in the long-distance injection group than in the routine group. The injection time (P=0.53), injection volume (P=0.78), number of supply arteries (P=0.80), Cognard types (P=0.67), and effect of embolization (P=0.88) were all similar between the two groups. CONCLUSION: Endovaseular treatment of intracranial DAVF with Onyx embolization using the long-distance injection method is feasible, safe and effective and can reduce the radiation exposure to the surgeon.